1. Field of the Invention
This invention relates to the use of .alpha..sub.1 -adrenoreceptor antagonists, or pharmaceutically acceptable acid addition salts, thereof for treating or preventing the formation of benign prostatic hyperplasia (BPH) in mammals. More particularly, it relates to a method for preventing the formation of, or reducing, BPH in mammals by administering to said mammals an .alpha..sub.1 -adrenoreceptor antagonist or pharmaceutically acceptable acid addition salt thereof.
2. General Background
Benign prostatic hyperplasia (BPH) is one of the most common, nonmalignant neoplastic processes to affect the aging man. Symptoms occur in about 50 and up to 80% of men 60 years old and older than 80 years, respectively. In the United States BPH is an important health problem resulting in an estimated 1.7 million visits to physicians offices each year.
BPH results from a progressive enlargement of the prostate, leading to urethral constriction, a disturbance in normal urinary outfow, urinary retention and associated irritative symptoms. In symptomatic BPH there appear to be two components of the urethral obstruction: a static component related to prostatic mass and a dynamic component related to the noradrenergic tone in the prostatic and urethral smooth muscle. A number of functional studies have shown that the contractile response is primarily mediated by .alpha..sub.1 -adrenoreceptors. Autoradiographical data suggest that these are primarily located on stromal smooth muscle.
Since approximately 50% of prostatic outflow obstruction in a patient is mediated by the sympathetic nervous system and, therefore, are potentially reversible it would be expected that urinary outflow obstruction and disease related symptoms would be relieved by .alpha..sub.1 -adrenoreceptor antagonists.
Early studies of phenoxybenzamine (a nonselective .alpha..sub.1 and .alpha..sub.2 adrenoreceptor antagonist) and prazosin (a selective .alpha..sub.1 -adrenoreceptor antagonist) were effective in in the treatment of BPH with the selective .alpha..sub.1 agent producing fewer and more tolerable side effects than the nonselective phenoxybenzamine. In a meta-analysis of literature data the .alpha..sub.1 -adrenoreceptor antagonists produced a 51% decrease in BPH symptom scores, improved urinary flow rate and post-void residual volume without increasing the risk of incontinence, impotence or other adverse effects associated with surgery for BPH.
Kenny, B. et al. (.alpha..sub.1 -Adrenoreceptor Antagonists As Treatments For Benign Prostatic Hyperplasia, Exp. Opin. Invest. Drugs, (1995), 4(10), 915-23), incorporated herein in its entirety by reference) have discussed the use of a number of .alpha..sub.1 -adrenoreceptor antagonists, such as terazosin, doxazosin and its 6'- and 7'-hydroxy metabolites, indoramin and tamsulosin forthe treatment of symptoms of BPH. However, they did not suggest that .alpha..sub.1 -adrenoreceptor antagonists could be used to prevent the formation of BPH or, if formed, treatment thereof to decrease the tumors.
Kaplan, S. A. et al, (Urology, 46(4), 1995, 512-17), Kirby, R. S. (Urology, 46(2), 1995, 182-6) and Fawzy, A. et al. (The Journal of Urology, 154 105-9 (1995)) have discussed the effect of doxasocin on the blood pressure of normotensive men who are being treated with doxazosin for mediation of the dynamic component of smooth muscle prostate outflow obstruction. However, they have not suggested that .alpha..sub.1 -adrenoreceptor antagonists could be used to prevent the formation of BPH or, if formed, treatment thereof to decrease the tumors.
Doxazosin, 4-amino-2-[4-(1-4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquin azoline and its pharmaceutically acceptable acid addition salts, are described in U.S. Pat. No. 4,188,390 together with their use as regulators of the cardiovascular system, especially in the treatment of hypertension.
U.S. Pat. No. 4,758,569 claims the use of doxazosin in retarding development of atherosclerosis in a mammal. The use of trimazosin or a pharmaceutically acceptable acid salt thereof, for retarding atherosclerosis is described and claimed in U.S. Pat. No. 4,582,832.
U.S. Pat. Nos. 4,868,216 and 4,987,152 claim the use of tamsulosin and its hydrochloride for producing .alpha..sub.1 -adrenoreceptor antagonistic action, or treating urinary tract dysfunction, respectively, in a host.
.alpha..sub.1 -Adrenoreceptor antagonists such as 2,4,6,7-tetrasubstituted quinazolines are disclosed in U.S. Pat. Nos. 3,511,836, 4,001,237 and 4,188,390 for use as hypertensive agents. U.S. Pat. No. 4,112,097 also claims the use of terazosin, and its tetrahydropyran-2-carbonyl homologue, for treatment of hypertension in mammals. The references do not disclose the use of those compounds for preventing the formation of, or reducing, BPH in a mammal.
Despite the many patents and studies, such as those above, relating to the use of .alpha..sub.1 -adrenoreceptor antagonists in the treatment of hypertension, atherosclerosis, urinary tract dysfunction and smooth muscle tone in BPH there has been no report or suggestion that .alpha..sub.1 -adrenoreceptor antagonists, or their pharmaceutically acceptable acid addition salts could be used to prevent the formation of, or reduce BPH in a mammal.
SUMMARY OF THE INVENTION
It has now been found that drugs consisting of .alpha..sub.1 -adrenoreceptor antagonists or their pharmaceutically acceptable acid addition salts, when administered to a mammal prior to the onset of BPH can prevent its formation or, after the onset of BPH, can reduce the condition. More specifically, the drugs, when administered in therapeutically effective doses, prevent formation of BPH or if BPH is already present they increase the rate of destruction (apoptosis) of the abnormal cells but do not affect normal cells. Preferably the .alpha..sub.1 -adrenoreceptor antagonists are selected from the group comprising alfuzosin, indoramin, terazosin, bunazosin, doxazosin and its 6'- and 7'-hydroxy metabolites, prazosin, tamsulosin, abanoquil, Recordati 15/2739 (trademark), RS 17053 (trademark), SL 89.0591 (trademark), other .alpha..sub.1 -adrenoreceptor antagonists mentioned by Kenny et al. (Id. at pages 917 and 919-20) and the like.